Substituted 3-hydroxy-δ-lactones (3HLs) are common structural motifs in natural products (Aggarwal et al., Tetrahedron 2004, 60, 9726-9733) and are valuable as intermediates in the synthesis of a variety of pharmaceutical compounds (Aggarwal et al., Tetrahedron 2004, 60, 9726-9733; Sharma et al., J. Org. Chem. 1999, 64, 8059-8062; Cefalo et al., J. Am. Chem. Soc. 2001, 123, 3139-3140; Stevenson, R.; Weber, J. V. J. Nat. Prod. 1988, 51, 1215-1219). 3HLs are most prominent in the class of HMG-CoA reductase inhibitors known as statins, which are among the most potent cholesterol-lowering drugs available and constitute five of the top 100 selling drugs (Tolbert et al., Nat. Rev. Drug. Discovery, 2003, 2, 517-526; de Lorenzo et al., Curr. Med. Chem. 2006, 13, 3385-3393). All approved statins have side chains comprised of either a 3HL or the hydrolyzed 3,5-dihydroxycarboxylic acid analog (FIG. 1), which are essential for the bioactivity of statin drugs (Aggarwal et al., Tetrahedron 2004, 60, 9726-9733). 3HLs have also been used in the synthesis of important drugs such as tetrahydrolipstatin (Sharma et al., J. Org. Chem. 1999, 64, 8059-8062), a lipase inhibitor prescribed for the treatment of obesity, and the antiretroviral agent tipranavir (Cefalo et al., J. Am. Chem. Soc. 2001, 123, 3139-3140). Furthermore, dehydration of 3HLs produces a class of biologically active α,β-unsaturated lactone natural products (Stevenson, R.; Weber, J. V. J. Nat. Prod. 1988, 51, 1215-1219).
As a result of their synthetic value, the synthesis of 3HLs has received a great deal of attention in recent years (Gijsen et al., J. Am. Chem. Soc. 1995, 117, 7585-7591; Heine et al., J. Mol. Biol. 2004, 343, 1019-1034; Loubinoux et al., Tetrahedron 1995, 51, 3549-3558; Kim et al., Synthesis 2001, 1790-1793; Le Sann et al., Org. Biomol. Chem. 2005, 3, 1719-1728; Reddy et al., J. Organomet. Chem. 2001, 624, 239-243; Fournier et al., Synlett 2003, 107-111). Biocatalytic routes have proven successful in the synthesis of statin side chains, though substrate scope is limited (Gijsen et al., J. Am. Chem. Soc. 1995, 117, 7585-7591; Heine et al., J. Mol. Biol. 2004, 343, 1019-1034). Synthetic routes to substituted 3HLs have employed a variety of methods, including aldol reactions using chiral auxiliaries, reduction of diketoesters followed by cyclization, allyl boration and ring-closing metathesis, and rearrangement of (3-lactones (Fournier et al., Synlett 2003, 107-111). These methods, however, involve multiple steps and can suffer from low stereoselectivity. Thus, there remains a need for improved methodologies to synthesize substituted 3-hydroxy-δ-lactones (3HLs). The present invention provides such a methodology.